ArticleBiomarker research2026
The NFIL3-MYC signaling axis: a novel therapeutic target and prognostic marker in high-risk multiple myeloma.
Article in Biomarker research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDrug resistance causes tumor relapse, limits the outcomes of patients with high-risk multiple myeloma (MM), and requires the development of targeted therapeutics. Increased Notch signaling promotes drug resistance in high-risk del(17p)/TP53-deficient clonogenic MM cells, highlighting the pathway and its downstream effectors as rational therapeutic targets in aggressive MM. However, the identification of selective, safe, and efficacious inhibitors targeting the Notch pathway remains a substantial challenge.
methodsTo identify novel druggable Notch effectors, we performed transcriptome profiling of Notch-depleted MM cells and selected potential candidates. We applied functional high-throughput shRNA library screens targeting these genes in MM cells with high Notch activity and under drug selection. Through bioinformatic analysis, we selected NFIL3 and validated its mechanistic specificity using ChIP-seq analysis, immunoblotting, cell viability and growth assays. We targeted NFIL3 via the oleanane-type triterpenoid saponin Raddeanin A (RA) and tested its efficacy in vivo using the murine MOPC.315.BM.Luc.eGFP-mCrbn
resultsIn functional genomics screens, we identified NFIL3 as a critical therapeutic vulnerability in high-risk, multidrug-resistant MM. Mechanistic studies silencing NFIL3 revealed that NFIL3 acts as a repressor of the MYC oncogenic driver in MM cells. RA collapsed the MYC-driven transcriptional program essential for MM cell survival and abrogated multidrug resistance of human and murine MM cells in vitro and in vivo. Importantly, the drug RA demonstrated potent anti-myeloma activity in patient-derived cells with high-risk cytogenetics following failure of BCMA-directed immunotherapies. Furthermore, high NFIL3 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease and was verified as an independent prognostic marker for overall survival in MM patients.
conclusionsRA targets the NFIL3-MYC axis and demonstrates potent anti-myeloma activity in vivo and in patient-derived high-risk MM cells following failure of BCMA-directed immunotherapies, providing a potent salvage strategy for multi-refractory disease.
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